1. Field of the invention
The present invention relates to novel diethylenetriamine pentaacetic acid (hereinafter, referred to as DTPA) derivatives and radioactive metal complex thereof as well as application of the latter in the diagnostic and therapeutic fields.
2. Background information
Substances labeled with .sup.131 I have been widely used in nuclear medicine for the detection of specific diseases, pharmacokinetic research and therapy of specific diseases using radioisotope. These substances, however, have many deficiencies such as (a) relatively long half-life of radioactivity, (b) emission of useless beta-rays besides gamma-rays, (c) radiation exposure of tissues other than a targetted tissue due to in vivo deiodination of .sup.131 I and the like.
In view of said deficiencies, the use of other radioactive metal elements such as .sup.111 In and .sup.99m Tc has been investigated as a substitute for .sup.131 I. These metal elements are usually used in a conjugated form with a carrier material comprising a ligand compound bonded to a physiologically active substance. In order to label physiologically active high molecular compounds such as fibrinogen, TPA (Tissue plasminogen activator), monoclonal antibodies and fragments thereof with radioisotopes (RI) as the metal elements, bifunctional chelating agents (BFC) have been widely utilized. Commonly used BFCs include anhydride (1) of DTPA, activated ester (2) thereof and ethylenediamine tetraacetic acid benzyl isothiocyanate (3). ##STR2##
In all cases, these BFCs are bonded to the physiologically active substances by amide bonding (--NHCO--). This means that the available and hence selectable bonding site is limited to amino groups. This also means that when the active site of the particular physiologically active substance contains lysine residue, a serious consequence such as loss of the physiological activity may occur. In addition, grave problems, high uptake and long retention of RI in normal liver cells, may occur when amide bonding is applied for labeling a monoclonal antibody with RI. The cause of this problem is entirely attributed to the fact that the bonding between BFCs and physiologically active substances is limited to amide bonding. More particularly, monoclonal antibodies are destined to be metabolized in normal liver cells. In this process RIs may dissociate from BFC-antibodies before the enzymatic cleavage of BFC-RI from the antibodies because of greater strength of the amide bond and retained as hydrolysates in liver cells. Since, however, BFC-RIs are water soluble complexes, even if they are cleaved from biologically active substances, they are secreted into the blood stream and then excreted through the kidney, thus raising no problem. Therefore, it has been found necessary to develop BFCs which can provide various bonding modes not limited to the amide bond.
On the other hand, the bonding modes between the biologically active substance and BFC-RI have also importance in obtaining better quality of diagnosis or therapeutic effect. For example, TPA has a very short activity half-life of only a few minutes in the blood stream. Therefore, when RI-labelled TPA is adopted for diagnosing blood clot, an RI having correspondingly shorter half-life such as .sup.99m Tc (T.sub.1/2 : 6 hours) should be selected, but .sup.99m Tc has a rather long half-life. Since the target tissue for TPA-BFC-RI is the vascular blood clot to which the administered TPA-BFC-RI binds when contacted, if inactivation of TPA in said TPA-BFC-RI precedes decay of RI, the inactivated-TPA-BFC-RI remains in the blood stream. This will adversely affect the quality of diagnosis. Therefore, a bonding mode which allows rapid cleavage of BFC-RI from inactivated TPA and hence rapid excretion is desirable. While an unstable bond is preferred to a stable bond in the above example, there may be other examples in which the above relation is reversed. For instance, in the diagnostic agent for imaging tumors containing lesser vascularity, it is essential or at least desirable that a certain amount of RI necessary for diagnosis contacts and binds to the tumor lesion and accumulate.
In these cases, relatively stable bonding modes are preferred. Of course, when the tumor to be diagnosed or treated contains much vascularity, stable bonding modes are not preferred. Accordingly, there is a strong and continuous need for development of BFC which allows wide selection of bonding mode.
There has been proposed an alternative approach, different from the use of above-mentioned BFCs (1), (2) and (3), in which a carrier is prepared by forming Schiff base of DTPA-mono-(2-aminoethyl)amide with oxidized inulin (aldehydic inulin), followed by reduction (J. Med. Chem. 31, 898-901, 1988). In this approach, however, the bonding modes of inulin are limited and therefore this approach is not satisfactory.
The DTPA-.sup.111 In complex has been used as a radioactive diagnostic agent. Aromatic amide derivative, i.e. 2-aminoethylanilide of DTPA was described in J. Labelled Comp. Radiopharm., 23, 1291 (1981).